tbuckley/cabot-search huggingface dataset:
Comparison of Germline Genetic Testing Before and After a Medical Policy Covering Universal Testing Among Patients With Colorectal Cancer
Authors: Chad Moretz, Stacey DaCosta Byfield, Kathryn E. Hatchell, Joline Dalton, Peter Nicholas Onglao, Lillian Hang, Pamela Hansen, Cristi Radford, Sarah M. Nielsen, Brandie Heald, Sandra B. Munro, Robert L. Nussbaum, Edward D. Esplin
Journal: JAMA Network Open (2022)

Importance In 2020, some health insurance plans updated their medical policy to cover germline genetic testing for all patients diagnosed with colorectal cancer (CRC). Guidelines for universal tumor screening via microsatellite instability and/or immunohistochemistry (MSI/IHC) for mismatch repair protein expression for patients with CRC have been in place since 2009. Objectives To examine whether uptake of MSI/IHC screening and germline genetic testing in patients with CRC has improved under these policies and to identify actionable findings and management implications for patients referred for germline genetic testing. Design, Setting, and Participants The multicenter, retrospective cohort study comprised 2 analyses of patients 18 years or older who were diagnosed with CRC between January 1, 2017, and December 31, 2020. The first analysis used an insurance claims data set to examine use of MSI/IHC screening and germline genetic testing for patients diagnosed with CRC between 2017 and 2020 and treated with systemic therapy. The second comprised patients with CRC who had germline genetic testing performed in 2020 that was billed under a universal testing policy. Main Outcomes and Measures Patient demographic characteristics, clinical information, and use of MSI/IHC screening and germline genetic testing were analyzed. Results For 9066 patients with newly diagnosed CRC (mean [SD] age, 64.2 [12.7] years; 4964 [54.8%] male), administrative claims data indicated that MSI/IHC was performed in 6645 eligible patients (73.3%) during the study period, with 2288 (25.2%) not receiving MSI/IHC despite being eligible for coverage. Analysis of a second cohort of 55 595 patients with CRC diagnosed in 2020 and covered by insurance found that only 1675 (3.0%) received germline genetic testing. In a subset of patients for whom germline genetic testing results were available, 1 in 6 patients had pathogenic or likely pathogenic variants, with most of these patients having variants with established clinical actionability. Conclusions and Relevance This nationwide cohort study found suboptimal rates of MSI/IHC screening and germline genetic testing uptake, resulting in clinically actionable genetic data being unavailable to patients diagnosed with CRC, despite universal eligibility. Effective strategies are required to address barriers to implementation of evidence-based universal testing policies that support precision treatment and optimal care management for patients with CRC.
Management of psychiatric and cognitive complications in Parkinson’s disease
Authors: Daniel Weintraub, Dag Aarsland, Roberta Biundo, Roseanne Dobkin, Jennifer Goldman, Simon Lewis,
Journal: BMJ (2022)

Abstract Neuropsychiatric symptoms (NPSs) such as affective disorders, psychosis, behavioral changes, and cognitive impairment are common in Parkinson’s disease (PD). However, NPSs remain under-recognized and under-treated, often leading to adverse outcomes. Their epidemiology, presentation, risk factors, neural substrate, and management strategies are incompletely understood. While psychological and psychosocial factors may contribute, hallmark PD neuropathophysiological changes, plus the associations between exposure to dopaminergic medications and occurrence of some symptoms, suggest a neurobiological basis for many NPSs. A range of psychotropic medications, psychotherapeutic techniques, stimulation therapies, and other non-pharmacological treatments have been studied, are used clinically, and are beneficial for managing NPSs in PD. Appropriate management of NPSs is critical for comprehensive PD care, from recognizing their presentations and timing throughout the disease course, to the incorporation of different therapeutic strategies (ie, pharmacological and non-pharmacological) that utilize a multidisciplinary approach.
Drugging KRAS: current perspectives and state-of-art review
Authors: Kaushal Parikh, Giuseppe Banna, Stephen V. Liu, Alex Friedlaender, Aakash Desai, Vivek Subbiah, Alfredo Addeo
Journal: Journal of Hematology & Oncology (2022)

Abstract After decades of efforts, we have recently made progress into targeting KRAS mutations in several malignancies. Known as the ‘holy grail’ of targeted cancer therapies, KRAS is the most frequently mutated oncogene in human malignancies. Under normal conditions, KRAS shuttles between the GDP-bound ‘off’ state and the GTP-bound ‘on’ state. Mutant KRAS is constitutively activated and leads to persistent downstream signaling and oncogenesis. In 2013, improved understanding of KRAS biology and newer drug designing technologies led to the crucial discovery of a cysteine drug-binding pocket in GDP-bound mutant KRAS G12C protein. Covalent inhibitors that block mutant KRAS G12C were successfully developed and sotorasib was the first KRAS G12C inhibitor to be approved, with several more in the pipeline. Simultaneously, effects of KRAS mutations on tumour microenvironment were also discovered, partly owing to the universal use of immune checkpoint inhibitors. In this review, we discuss the discovery, biology, and function of KRAS in human malignancies. We also discuss the relationship between KRAS mutations and the tumour microenvironment, and therapeutic strategies to target KRAS. Finally, we review the current clinical evidence and ongoing clinical trials of novel agents targeting KRAS and shine light on resistance pathways known so far.
New NIH Program for Artificial Intelligence in Research
Authors: Melissa Suran
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Analysis of Blood Culture Collection and Laboratory Processing Practices in Israel
Authors: Elizabeth Temkin, Dikla Biran, Tali Braun, David Schwartz, Yehuda Carmeli
Journal: JAMA Network Open (2022)

Blood culturing is a critical diagnostic procedure affecting patient outcomes and antibiotic stewardship. Although there are standards for blood culturing, the process is not often measured.To evaluate processes related to the diagnosis of bloodstream infection and compare them with best practices.A quality improvement study using laboratory data from January 1 to June 30, 2019, was conducted in 28 (96.6%) Israeli acute care hospitals. All blood cultures (BCs) performed on samples from adults and children in a period of 147 hospital-months were analyzed. Data analysis was performed from April 12, 2021, to September 9, 2022.True pathogen detection rate, contamination rate, proportion of adults with blood cultures performed, proportion of adult culturing episodes with only 1 set or bottle used, and median time of steps from sample collection to pathogen identification.The data set consisted of 348 987 BC bottles. Bloodstream infection was detected in a median of 6.7% (IQR, 5.8%-8.2%) of adult culturing episodes and 1.1% (IQR, 0.7%-1.9%) of pediatric episodes. Eleven of 27 hospitals (40.7%) with adult patients met the standard of a contamination rate of less than 3% and only 2 hospitals (7.4%) met the more stringent standard of less than or equal to 1% contamination rate. The percentage of adults with blood cultures ranged from 2.7% to 29.0% (mean [SD], 15.7% [6.0%]). There was an association between sampling rate and pathogen detection until BCs were performed in 17% of adult admissions. The percentage of solitary BCs ranged from 47.8% to 94.4%. An estimated 1745 of 7436 (23.5%) adult bloodstream infections went undetected because solitary BCs were performed, anaerobic bottles were not used, or BCs were not performed. Median processing time was 51.2 (IQR, 33.9-78.0) hours, 3 times the optimal time: 4.4 (IQR, 1.7-12.5) hours for the preanalytical stage, 15.9 (IQR, 10.2-23.6) hours from incubation to growth detection, 4.5 (IQR, 1.5-10.7) hours from detection to Gram stain, and 30.9 (IQR, 22.0-41.9) hours from detection to isolate identification. An 8.6-hour delay was related to off-hours operating of laboratories.The findings of this study suggest that the multistep process of blood culturing is not managed comprehensively in Israel, leading to poor clinical practices and delayed results.
Hypercalcemia
Authors: Marcella Donovan Walker, Elizabeth Shane
Journal: JAMA (2022)

Importance Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (&amp;amp;lt;3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (&amp;amp;gt;3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma. Observations Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (&amp;amp;lt;20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival. Conclusions and Relevance Mild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.
Sacubitril-Valsartan and Heart Function in End-stage Kidney Disease
Authors: Anita Slomski
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Pharmacological Landscape of FDA-Approved Anticancer Drugs Reveals Sensitivities to Ixabepilone, Romidepsin, Omacetaxine, and Carfilzomib in Aggressive Meningiomas
Authors: Gerhard Jungwirth, Tao Yu, Fang Liu, Junguo Cao, Montadar Alaa Eddine, Mahmoud Moustafa, Amir Abdollahi, Rolf Warta, Andreas Unterberg, Christel Herold-Mende
Journal: Clinical Cancer Research (2022)

Abstract Purpose: To date, there are no systemic treatment options for patients with recurrent or refractory meningioma. Experimental Design: To identify effective drugs, we performed a large-scale drug screening using FDA-approved drugs on several meningioma cell lines. The impact of the top four compounds was assessed on cell viability, proliferation, colony formation, migration, and apoptosis. In addition, the antineoplastic effects of the selected drugs were validated in a heterotopic xenograft mouse model. Results: Analyses of the viability of meningioma cells treated with 119 antineoplastic FDA-approved drugs resulted in categorization into sensitive and resistant drug–response groups based on the mean IC50 values and peak serum concentrations (Cmax) in patients. Eighty drugs, including 15 alkylating agents, 14 antimetabolites, and 13 tyrosine kinase inhibitors, were classified as resistant (IC50 &amp;gt; Cmax). The sensitive drug–response group (n = 29, IC50 &amp;lt; Cmax) included RNA/protein synthesis inhibitors, proteasome inhibitors, topoisomerase, tyrosine-kinase, and partial histone deacetylase and microtubule inhibitors. The IC50 value of the four most effective compounds (carfilzomib, omacetaxine, ixabepilone, and romidepsin) ranged from 0.12 to 9.5 nmol/L. Most of them caused cell-cycle arrest in the G2–M-phase and induced apoptosis. Furthermore, all drugs except romidepsin significantly inhibited tumor growth in vivo. The strongest antineoplastic effect was observed for ixabepilone, which reduced tumor volume by 86%. Conclusions: In summary, a large-scale drug screening provides a comprehensive insight into the anti-meningioma activities of FDA-approved drugs, and identified carfilzomib, omacetaxine, ixabepilone, and romidepsin as novel potent antineoplastic agents for the treatment of aggressive meningiomas. The most pronounced effects were observed with ixabepilone mandating for further clinical investigation.
Letting Go
Authors: Wynne Morrison
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Assessment of Cystatin C Level for Risk Stratification in Adults With Chronic Kidney Disease
Authors: Jennifer S. Lees, Elaine Rutherford, Kathryn I. Stevens, Debbie C. Chen, Rebecca Scherzer, Michelle M. Estrella, Michael K. Sullivan, Natalie Ebert, Patrick B. Mark, Michael G. Shlipak
Journal: JAMA Network Open (2022)

Importance Kidney function is usually estimated from serum creatinine level, whereas an alternative glomerular filtration marker (cystatin C level) associates more closely with future risk of cardiovascular disease (CVD) and mortality. Objectives To evaluate whether testing concordance between estimated glomerular filtration rates based on cystatin C (eGFRcys) and creatinine (eGFRcr) levels would improve risk stratification for future outcomes and whether estimations differ by age. Design, Setting, and Participants A prospective population-based cohort study (UK Biobank), with participants recruited between 2006-2010 with median follow-up of 11.5 (IQR, 10.8-12.2) years; data were collected until August 31, 2020. Participants had eGFRcr greater than or equal to 45 mL/min/1.73 m 2 , albuminuria (albumin &amp;amp;lt;30 mg/g), and no preexisting CVD or kidney failure. Exposures Chronic kidney disease status was categorized by concordance between eGFRcr and eGFRcys across the threshold for hronic kidney disease (CKD) diagnosis (60 mL/min/1.73 m 2 ). Main Outcomes and Measures Ten-year probabilities of CVD, mortality, and kidney failure were assessed according to CKD status. Multivariable-adjusted Cox proportional hazards models tested associations between CVD and mortality. Area under the receiving operating curve tested discrimination of eGFRcr and eGFRcys for CVD and mortality. The Net Reclassification Index assessed the usefulness of eGFRcr and eGFRcys for CVD risk stratification. Analyses were stratified by older (age 65-73 years) and younger (age &amp;amp;lt;65 years) age. Results There were 428 402 participants: median age was 57 (IQR, 50-63) years and 237 173 (55.4%) were women. Among 76 629 older participants, there were 9335 deaths and 5205 CVD events. Among 351 773 younger participants, there were 14 776 deaths and 9328 CVD events. The 10-year probability of kidney failure was less than 0.1%. Regardless of the eGFRcr, the 10-year probabilities of CVD and mortality were low when eGFRcys was greater than or equal to 60 mL/min/1.73 m 2 ; conversely, with eGFRcys less than 60 mL/min/1.73 m 2 , 10-year risks were nearly doubled in older adults and more than doubled in younger adults. Use of eGFRcys better discriminated CVD and mortality risk than eGFRcr. Across a 7.5% 10-year risk threshold for CVD, eGFRcys improved case Net Reclassification Index by 0.7% (95% CI, 0.6%-0.8%) in older people and 0.7% (95% CI, 0.7%-0.8%) in younger people; eGFRcr did not add to CVD risk estimation. Conclusions and Relevance The findings of this study suggest that eGFRcr 45 to 59 mL/min/1.73 m 2 includes a proportion of individuals at low risk and fails to capture a substantial proportion of individuals at high-risk for CVD and mortality. The eGFRcys appears to be more sensitive and specific for CVD and mortality risks in mild CKD.
Immune checkpoint of B7-H3 in cancer: from immunology to clinical immunotherapy
Authors: Binghao Zhao, Huanzhang Li, Yu Xia, Yaning Wang, Yuekun Wang, Yixin Shi, Hao Xing, Tian Qu, Yu Wang, Wenbin Ma
Journal: Journal of Hematology & Oncology (2022)

Immunotherapy for cancer is a rapidly developing treatment that modifies the immune system and enhances the antitumor immune response. B7-H3 (CD276), a member of the B7 family that plays an immunoregulatory role in the T cell response, has been highlighted as a novel potential target for cancer immunotherapy. B7-H3 has been shown to play an inhibitory role in T cell activation and proliferation, participate in tumor immune evasion and influence both the immune response and tumor behavior through different signaling pathways. B7-H3 expression has been found to be aberrantly upregulated in many different cancer types, and an association between B7-H3 expression and poor prognosis has been established. Immunotherapy targeting B7-H3 through different approaches has been developing rapidly, and many ongoing clinical trials are exploring the safety and efficacy profiles of these therapies in cancer. In this review, we summarize the emerging research on the function and underlying pathways of B7-H3, the expression and roles of B7-H3 in different cancer types, and the advances in B7-H3-targeted therapy. Considering different tumor microenvironment characteristics and results from preclinical models to clinical practice, the research indicates that B7-H3 is a promising target for future immunotherapy, which might eventually contribute to an improvement in cancer immunotherapy that will benefit patients.